Compressed tablets comprising microcapsules with modified release

• US 20050266078A1
• Filed: 03/14/2003
• Published: 12/01/2005
• Est. Priority Date: 03/18/2002
• Status: Active Grant

• Current Assignee: Flamel Ireland, Ltd.
• Original Assignee: Flamel Technologies SA (Avadel Pharmaceuticals Plc)
• Inventors: Autant, Pierre, Jorda, Rafael
• Granted Patent: US 8,507,003 B2
• Time in Patent Office: Days
• US Class Current: 424/471
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings

Abstract

A multi(micro)particulate tablet is provided comprising microparticles which comprise a mechanically non-deformable core of active principle (AP). The tablet is formed from reservoir microcapsules with prolonged release of the AP, which are each made up of a non-deformable core comprising AP and covered with at least one film coating controlling release of the AP in vivo. The microcapsules have a particle size of between 50 and 1000 microns and are coated with at least one outer overcoating envelope comprising at least one deformable organic constituent having a melting point of between 40° C. and 120° C. The envelope allows the prolonged release of the AP in vivo without modification of the release profile when the microcapsules are compressed to form a tablet, even for microparticles not specifically formulated for compression.

Claims

1-17. -17. (canceled)

18. A tablet providing prolonged release in vivo of at least one active principle (AP), comprising microcapsules having a particle size of between 50 and 1000 microns, wherein the microcapsules comprise a non-deformable core and at least one outer overcoating envelope, the non-deformable core comprising the at least one AP covered with at least one film coating controlling the prolonged release of the AP in vivo;

and the at least one outer overcoating envelope comprising at least one deformable organic constituent having a melting point of between 40°

C. and 120°

C., wherein the envelope provides mechanical strength during compression without affecting the prolonged release properties of the at least one film coating of the non-deformable core.

19. The tablet according to claim 18, which is orally dispersible.

20. The tablet according to claim 18, wherein the microcapsules have a particle size of between 100 and 750 microns.

21. The tablet according to claim 18, wherein the microcapsules have a particle size of between 200 and 500 microns.

22. The tablet according to claim 18, wherein the at least one outer overcoating envelope comprises at least 10% by weight of at least one deformable organic constituent.

23. The tablet according to claim 18, wherein the at least one deformable organic constituent has a melting point of between 45°

C. and 100°

C.

24. The tablet according to claim 18, wherein the at least one deformable organic constituent is an alkylene glycol.

25. The tablet according to claim 18, wherein the at least one deformable organic constituent is a polyalkylene glycol.

26. The tablet according to claim 18, wherein the at least one deformable organic constituent is a polyalkylene glycol having a molecular weight of between 6000 to 20,000 D.

27. The tablet according to claim 18, wherein the at least one deformable organic constituent is a fat or mixture of fats.

28. The tablet according to claim 18, wherein the at least one deformable organic constituent is a hydrogenated vegetable oil, fatty acid, fatty alcohol, fatty acid ester, fatty alcohol ester, polyolefin, mineral wax, vegetable wax, animal wax, synthetic wax, or mixture thereof.

29. The tablet according to claim 18, wherein the at least one deformable organic constituent is a fatty acid ester.

30. The tablet according to claim 18, wherein the at least one deformable organic constituent is a diglyceride, triglyceride, mixture of a diglyceride and a triglyceride, glycerol behenate, hydrogenated castor oil, hydrogenated soya bean oil, hydrogenated cottonseed oil, or hydrogenated palm oil.

31. The tablet according to claim 18, wherein the at least one outer overcoating envelope further comprises one or more of a mineral filler, an organic filler, a lubricant, a hydrophilic polymer, or a surfactant.

32. The tablet according to claim 31, wherein the mineral filler is silica or titanium dioxide.

33. The tablet according to claim 31, wherein the organic filler is microcrystalline cellulose.

34. The tablet according to claim 31, wherein the lubricant is magnesium stearate or sodium benzoate.

35. The tablet according to claim 31, wherein the hydrophilic polymer is a water-soluble cellulose derivative.

36. The tablet according to claim 31, wherein the hydrophilic polymer is hydroxypropyl cellulose or hydroxypropyl methyl cellulose.

37. The tablet according to claim 31, wherein the hydrophilic polymer is a synthetic polymer.

38. The tablet according to claim 31, wherein the hydrophilic polymer is polyvinylpyrrolidone or polyvinyl alcohol (PVA).

39. The tablet according to claim 31, wherein the hydrophilic polymer is an acrylic derivative or a methacrylic derivative.

40. The tablet according to claim 18, wherein the outer overcoating envelope comprises from 5 to 50% of the total dry weight of the microcapsules.

41. The tablet according to claim 18, wherein the outer overcoating envelope comprises from 10 to 30% of the total dry weight of the microcapsules.

42. The tablet according to claim 18, wherein the outer overcoating envelope comprises in the order of 20% of the total dry weight of the microcapsules.

43. The tablet according to claim 18, wherein the film coating of the microcapsules comprises:

at least one film-forming polymer (P1) comprising a water-insoluble cellulose derivative, wherein P1 is insoluble in the tract fluids and present in an amount of 50 to 90% by dry weight, based on the total weight of the coating composition;

at least one nitrogen-containing polymer (P2) comprising polyacrylamide, poly-N-vinylamide, poly-N-vinyllactam, or a mixture thereof, wherein P2 is present in an amount of 2 to 25% by dry weight, based on the total weight of the coating composition;

at least one plasticizer comprising a glycerol ester, a phthalate, a citrate, a sebacate, a cetyl alcohol ester, castor oil, salicylic acid, cutin, or a mixture thereof, wherein the plasticizer is present in an amount of 2 to 20% by dry weight, based on the total weight of the coating composition; and

at least one anionic surfactant, non-ionic surfactant, lubricant, or mixture thereof present in an amount of 2 to 20% by dry weight, based on the total weight of the coating composition.

44. The tablet according to claim 43, wherein P1 is present in an amount of 50 to 80% by dry weight of the coating composition.

45. The tablet according to claim 43, wherein P1 is ethylcellulose, cellulose acetate, or a mixture thereof.

46. The tablet according to claim 43, wherein P2 is present in an amount of 5 to 15% by dry weight of the coating composition.

47. The tablet according to claim 43, wherein P2 is polyacrylamide, polyvinylpyrrolidone, or a mixture thereof.

48. The tablet according to claim 43, wherein the plasticizer is present in an amount of 4 to 15% by dry weight of the coating composition.

49. The tablet according to claim 43, wherein the plasticizer is castor oil.

50. The tablet according to claim 43, wherein the surfactant is present in an amount of 4 to 15% by dry weight of the coating composition.

51. The tablet according to claim 43, wherein the anionic surfactant is an alkali metal salt of a fatty acid or an alkaline earth metal salt of a fatty acid;

the non-ionic surfactant is a polyethoxylated sorbitan ester, a polyethoxylated castor oil derivative, or a mixture thereof; and

the lubricant is calcium stearate, magnesium stearate, aluminium stearate, zinc stearate, a stearylfumarate, glycerol behenate, or a mixture thereof.

52. The tablet according to claim 18, wherein the film coating of the microcapsules comprises from 60 to 80% of ethyl cellulose, from 5 to 10% of polyvinylpyrrolidone, from 5 to 10% of castor oil and 2 to 8% of magnesium stearate.

53. The tablet according to claim 18, wherein the microcapsules have the following composition by weight:

core comprising the AP;

from 50 to 80% by dry weight,

film coating;

from 10 to 30% by dry weight, and

overcoating envelope;

from 10 to 30% by dry weight.

54. The tablet according to claim 18, wherein the microcapsules have the following composition by weight:

core comprising the AP;

from 55 to 65% by dry weight,

film coating;

from 15 to 25% by dry weight, and

overcoating envelope;

from 15 to 25% by dry weight.

55. The tablet according to claim 18, wherein the overcoated microcapsules comprise the AP in an amount greater than or equal to 50% of their total dry weight.

56. The tablet according to claim 18, wherein the hardness of the tablet is greater than or equal to 20 N.

57. The tablet according to claim 18, wherein the AP is an antiulcer drug, antidiabetic, anticoagulant, antithrombic, hypolipidaemic, antiarrhythmic, vasodilator, antiangina drug, antihypertensive, vasoprotector, fertility promoter, labour inducer, labour inhibitor, contraceptive, antibiotic, antifungal, antiviral, anticancer drug, antiinflammatorie, analgesic, antiepileptic, antiparkinsonism drug, neuroleptic, hypnotic, anxiolytic, psychostimulant, antimigraine drug, antidepressant, antitussive, antihistamine, or antiallergic.

58. The tablet according to claim 18, wherein the AP is pentoxifylline, prazosin, aciclovir, nifedipine, diltiazem, naproxen, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, indomethacin, diclofenac, fentiazac, oestradiol valerate, metoprolol, sulpiride, captopril, cimetidine, zidovudine, nicardipine, terfenadine, atenolol, salbutamol, carbamazepine, ranitidine, enalapril, simvastatin, fluoxetine, alprazolam, famotidine, ganciclovir, famciclovir, spironolactone, 5-asa, quinidine, perindopril, morphine, pentazocine, paracetamol, aspirin, metformin, omeprazole, metoclopramide, or a mixture thereof.

59. The tablet according to claim 18, wherein the AP is a nutritional supplement, dietetic supplement, or a mixture thereof.

60. The tablet according to claim 18, wherein the AP is a vitamin, amino acid, trace element, antioxidant, or mixture thereof.

63. A method for preparing the tablet according to claim 18, comprising coating a non-deformable core with at least one outer overcoating envelope to prepare overcoated microcapsules having a particle size of between 50 and 1000 microns, and compressing the overcoated microcapsules to form a tablet;

wherein the non-deformable core comprises at least one AP and is covered with at least one film coating controlling the prolonged release of the AP in vivo; and

wherein the at least one outer overcoating envelope comprises at least one deformable organic constituent having a melting point of between 40°

C. and 120°

C. and provides mechanical strength during compression without affecting the prolonged release properties of the at least one film coating of the non-deformable core.

64. A method for achieving the prolonged release of at least one active principle in vivo, comprising administering to a patient in need thereof the tablet according to claim 18.

61. A microcapsule providing prolonged release in vivo of at least one active principle (AP), wherein the microcapsule has a particle size of between 50 and 1000 microns and comprises a non-deformable core and at least one outer overcoating envelope;

wherein the non-deformable core comprises at least one AP and is covered with at least one film coating controlling the prolonged release of the AP in vivo; and

wherein the at least one outer overcoating envelope comprises at least one deformable organic constituent having a melting point of between 40°

C. and 120°

C. and provides mechanical strength during compression without affecting the prolonged release properties of the at least one film coating of the non-deformable core.

62. A method for preparing the microcapsule according to claim 61, comprising coating a non-deformable core with at least one outer overcoating envelope to prepare overcoated microcapsules having a particle size of between 50 and 1000 microns;

wherein the non-deformable core comprises at least one AP and is covered with at least one film coating controlling the prolonged release of the AP in vivo; and

wherein the at least one outer overcoating envelope comprises at least one deformable organic constituent having a melting point of between 40°

C. and 120°

C. and provides mechanical strength during compression without affecting the prolonged release properties of the at least one film coating of the non-deformable core.